Project Summary/Abstract: Neuropathology Core The overall objective of the Neuropathology Core of the University of Kentucky Alzheimer?s Disease Center (UK-ADC) is to support research on normal brain aging, presymptomatic Alzheimer?s disease (pAD), mild cognitive impairment (MCI), early and late AD, mixed dementia syndromes, and other dementing disorders. Autopsies will be performed by our Rapid Autopsy Team on longitudinally followed subjects from our Clinical Core. We will perform short post-mortem interval autopsies in relation to our clinical cohort, and we will maintain a high autopsy rate. This Core is optimally tailored to help address important research questions. The Core will provide brain tissue specimens, CSF and synaptosomes for investigators at UK, other ADCs, and outside investigators. The Core will also provide consensus conference determined diagnoses, quantitation of neurofibrillary tangles (NFT), neuritic plaques, and diffuse plaques from 8 brain regions, A? 1-40 and 1-42 quantitation, Braak staging, CERAD, and NIA-Reagan Institute staging on all autopsied cases to investigators. This brain bank has been operating continuously for over three decades with a strong track record, so special care will be taken to ensure diagnostic excellence, consistency, and continuity. The Core will maintain a tissue bank of the above specimens and frozen serum, plasma, buffy coats and CSF from living patients. Special emphasis will be placed on defining the neuropathological findings in the brains of the oldest old (>85 years), and providing investigators with specimens from cognitively intact control subjects with no A? deposition and sparse tau pathology (successful cerebral aging) and also cognitively intact subjects with abundant plaques and neurofibrillary tangles. Providing these samples will contribute to clinical-pathological correlation studies and cutting-edge research that include sponsored studies related to AD genomics, oxidative stress, hippocampal sclerosis, dementia with Lewy bodies, amyloid precursor protein processing, Down syndrome, and neuroinflammation. Frequent consensus conferences will be held with the Clinical Core and Biostatistics Core to help define clinical-pathological diagnoses on all autopsied subjects. This Core is strongly integrated with other Cores of the UK-ADC, and exploits unique opportunities to conduct clinical-pathological correlative studies on longitudinally followed subjects. Through these methods we will better understand normal brain aging and the transition to dementia with the focused goal of contributing to therapeutic or preventive measures. The Neuropathology Core complements the other Cores of the UK-ADC to provide extremely essential diagnoses and tissue samples that are required for many cutting-edge researchers at the University of Kentucky and elsewhere. We will build on our track record of excellence using innovative tools related to brain autopsies, neuropathological diagnoses, tissue banking, and state-of-the-art clinical-pathological correlation.